Efficacy and safety is paramount in the treatment of disease states with therapeutically active agents. Efficacy is usually as a result of the therapeutic agent reaching its target sites in amounts sufficient to maintain therapeutic levels for a desired period. It is now generally accepted that sustained release of a therapeutically active agent is desirable when treating chronic diseases conditions were current therapy dictates multiple daily dosing and were the half life of the therapeutic agent is short. With traditional sustained-release dosage formulations, particularly matrix based systems, when taken in the morning, the efficacy of the therapeutic agent diminishes at the end of the night and the beginning of the next day.
When therapeutics agents are administered orally they must enter the general circulation of the human body in order to reach their target sites of action. They are released in the GIT, and are absorbed into the capillaries and veins of the upper gastrointestinal tract, and transported by the portal vein to the liver. Following their absorption in the intestine, some orally administered therapeutic agents may be subject to a “first pass” clearance by the liver and excreted into bile or converted into pharmacologically inactive metabolites. This can result in a decrease in bioavailability due to the liver removing the therapeutic agent from the bloodstream prior to entering a patient's general circulation. For a therapeutic agent to overcome a first pass effect it has to be present in amounts that exceed the excretory or metabolic capability of the liver.
First pass metabolism makes it difficult to the maintain therapeutic levels of an orally administered therapeutic agent over an extended period such as 12 or 24 hours.
One way to overcome this problem is to administer formulations capable of immediate drug release multiple times daily (i.e., 2-4 times daily), but this approach may result in high peaks and low valley effects (i.e., toxic and sub-therapeutic levels) and compliance issues. Another way is to administer formulations, capable of sustained drug release, that are suitable for once-daily administration. Due to the need to reduce the difference between “peak and valley” concentrations and patient compliance issues, once-daily sustained release formulations are preferred. A sustained release formulation, however, may subject the patient to toxic drug levels over part of the dosing period, and sub-therapeutic drug levels over other portions of the dosing period, if the drug release does not occur at appropriate time intervals. The maintenance of therapeutic levels of an orally administered drug over an extended period thus depends upon a drug delivery system capable of providing an appropriate release profile.
It can be seen from the foregoing that there is a need in the art to develop a controlled extended drug release technology with or without a loading dose in a tablet, pellet or bead formulation suitable for a more precise zero, first or pseudo first order release of a therapeutic agent, and which, in situations where the drug is subject to “first pass” metabolism, can be used to provide sustained drug delivery, preferably over a 24-hour period, by an amount sufficient to exceed the liver's metabolic capacity and to maintain therapeutic levels.
It was unexpectedly discovered that controlled extended release technology can be used to improve the efficacy of therapeutic agents during the declining phase identified above.